Chromosome-level organization of the regulatory genome in the Drosophila nervous system.

Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.

Drosophila SPG12 ortholog, reticulon-like 1, governs presynaptic ER organization and Ca2+ dynamics.

Neuronal endoplasmic reticulum (ER) appears continuous throughout the cell. Its shape and continuity are influenced by ER-shaping proteins, mutations in which can cause distal axon degeneration in Hereditary Spastic Paraplegia (HSP). We therefore asked how loss of Rtnl1, a Drosophila ortholog of the human HSP gene RTN2 (SPG12), which encodes an ER-shaping protein, affects ER organization and the function of presynaptic terminals. Loss of Rtnl1 depleted ER membrane markers at Drosophila presynaptic motor terminals and appeared to deplete narrow tubular ER while leaving cisternae largely unaffected, thus suggesting little change in resting Ca2+ storage capacity. Nevertheless, these changes were accompanied by major reductions in activity-evoked Ca2+ fluxes in the cytosol, ER lumen, and mitochondria, as well as reduced evoked and spontaneous neurotransmission. We found that reduced STIM-mediated ER-plasma membrane contacts underlie presynaptic Ca2+ defects in Rtnl1 mutants. Our results show the importance of ER architecture in presynaptic physiology and function, which are therefore potential factors in the pathology of HSP.

Swallowing Preparation and Execution: Insights from a Delayed-Response Functional Magnetic Resonance Imaging (fMRI) Study.

The present study sought to elucidate the functional contributions of sub-regions of the swallowing neural network in swallowing preparation and swallowing motor execution. Seven healthy volunteers participated in a delayed-response, go, no-go functional magnetic resonance imaging study involving four semi-randomly ordered activation tasks: (i) "prepare to swallow," (ii) "voluntary saliva swallow," (iii) "do not prepare to swallow," and (iv) "do not swallow." Results indicated that brain activation was significantly greater during swallowing preparation, than during swallowing execution, within the rostral and intermediate anterior cingulate cortex bilaterally, premotor cortex (left > right hemisphere), pericentral cortex (left > right hemisphere), and within several subcortical nuclei including the bilateral thalamus, caudate, and putamen. In contrast, activation within the bilateral insula and the left dorsolateral pericentral cortex was significantly greater in relation to swallowing execution, compared with swallowing preparation. Still other regions, including a more inferior ventrolateral pericentral area, and adjoining Brodmann area 43 bilaterally, and the supplementary motor area, were activated in relation to both swallowing preparation and execution. These findings support the view that the preparation, and subsequent execution, of swallowing are mediated by a cascading pattern of activity within the sub-regions of the bilateral swallowing neural network.

The relationship between visual-spatial and auditory-verbal working memory span in Senegalese and Ugandan children.

BACKGROUND: Using the Kaufman Assessment Battery for Children (K-ABC) Conant et al. (1999) observed that visual and auditory working memory (WM) span were independent in both younger and older children from DR Congo, but related in older American children and in Lao children. The present study evaluated whether visual and auditory WM span were independent in Ugandan and Senegalese children. METHOD: In a linear regression analysis we used visual (Spatial Memory, Hand Movements) and auditory (Number Recall) WM along with education and physical development (weight/height) as predictors. The predicted variable in this analysis was Word Order, which is a verbal memory task that has both visual and auditory memory components. RESULTS: Both the younger (<8.5 yrs) and older (>8.5 yrs) Ugandan children had auditory memory span (Number Recall) that was strongly predictive of Word Order performance. For both the younger and older groups of Senegalese children, only visual WM span (Spatial Memory) was strongly predictive of Word Order. Number Recall was not significantly predictive of Word Order in either age group. CONCLUSIONS: It is possible that greater literacy from more schooling for the Ugandan age groups mediated their greater degree of interdependence between auditory and verbal WM. Our findings support those of Conant et al., who observed in their cross-cultural comparisons that stronger education seemed to enhance the dominance of the phonological-auditory processing loop for WM.

Differentiating effortful and noneffortful swallowing with a neck force transducer: implications for the development of a clinical feedback system.

This study sought to determine whether effortful saliva swallows could be differentiated from habitual, noneffortful saliva swallows on the basis of swallow-related changes in neck circumference in humans. Gender differences in swallow-related neck circumference were examined as a secondary question. Twenty-seven healthy adults (14 females; mean age = 26.6 years, SD = 3.9 years) participated in two experimental runs (run duration = 10 min) during which they produced single trials of three visually cued tasks in random order: effortful saliva swallowing, saliva swallowing, and a control task involving repetitive apposition of the dominant thumb and index finger. Neck and ribcage circumference were simultaneously collected from the output of force transducers positioned around the neck and ribcage, respectively. The primary outcome variables were the positive and negative voltage peak amplitudes associated with changes in neck circumference during single-swallow trials. Effects of the swallowing task on positive and negative voltage peaks were examined with separate two-way analysis of variance procedures. Results indicated that both positive (F = 6.49, p < 0.05) and negative (F = 12.05, p

Bolus location at the initiation of the pharyngeal stage of swallowing in healthy older adults.

This study characterized the vertical position of the bolus head at the onset of the pharyngeal swallow in healthy older adults. Lateral-view videofluoroscopic (VF) images were obtained from ten healthy volunteers (age-71.6 +/- 7.5 years, mean+/- SD) as they swallowed 5-cc thin liquid barium aliquots. For each swallow, the bolus head and several anatomic landmarks were digitally recorded from the image in which pharyngeal swallow-related hyoid bone elevation began. Vertical distance between the bolus head and the intersection of the tongue base and mandibular ramus (TMI) was computed. Bolus head position at swallow onset ranged from 47.4-mm above to 34.9-mm below the TMI (2.2 +/- 14.4-mm, mean +/- SD). Although the bolus head was below the level of the TMI for the majority of swallows, neither penetration nor aspiration occurred. For individual subjects, mean bolus head position ranged from 25.8 +/- 5.0-mm above to 15.5 +/- 6.5-mm below the TMI. Whereas five of ten subjects initiated the pharyngeal swallow with the bolus head consistently above or consistently below the TMI, five subjects initiated swallowing with the bolus head either above or below the TMI across trials. Older adults commonly initiate thin-liquid swallows with the bolus head well below the TMI without associated penetration or aspiration. Thus, bolus position alone does not differentiate between normal and pathologic swallowing within the healthy elderly. Bolus position at pharyngeal swallow onset can vary substantially from trial to trial within an individual, suggesting that the triggering of swallowing depends on multiple influences.

Cerebral areas processing swallowing and tongue movement are overlapping but distinct: a functional magnetic resonance imaging study.

Although multiple regions of the cerebral cortex have been implicated in swallowing, the functional contributions of each brain area remain unclear. The present study sought to clarify the roles of these cortical foci in swallowing by comparing brain activation associated with voluntary saliva swallowing and voluntary tongue elevation. Fourteen healthy right-handed subjects were examined with single-event-related functional magnetic resonance imaging (fMRI) while laryngeal movements associated with swallowing and tongue movement were simultaneously recorded. Both swallowing and tongue elevation activated 1) the left lateral pericentral and anterior parietal cortex, and 2) the anterior cingulate cortex (ACC) and adjacent supplementary motor area (SMA), suggesting that these brain regions mediate processes shared by swallowing and tongue movement. Tongue elevation activated a larger total volume of cortex than swallowing, with significantly greater activation within the ACC, SMA, right precentral and postcentral gyri, premotor cortex, right putamen, and thalamus. Although a contrast analysis failed to identify activation foci specific to swallowing, superimposed activation maps suggested that the most lateral extent of the left pericentral and anterior parietal cortex, rostral ACC, precuneus, and right parietal operculum/insula were preferentially activated by swallowing. This finding suggests that these brain areas may mediate processes specific to swallowing. Approximately 60% of the subjects showed a strong functional lateralization of the postcentral gyrus toward the left hemisphere for swallowing, whereas 40% showed a similar activation bias for the tongue elevation task. This finding supports the view that the oral sensorimotor cortices within the left and right hemispheres are functionally nonequivalent.